Structure-activity relationship in the case of intramolecular ortho-cyclization of aromatic nitroso oxides: Inverted steric effect of substituent in the 2-R-C6H4NOO transformation

A systematic theoretical study at the M06L/6-311+G(d, p) level of theory was carried out to calculate the activation barriers ΔH^≠ for the intramolecular ortho-cyclization of aromatic nitroso oxides 2-R-C₆H₄NOO and to reveal the effect of substituent nature and position in the benzene ring on the nitroso oxides reactivity. A set of 24 substituents with widely differing spatial and electronic properties (inductive, resonant, steric effects of R) was studied. The para-substituent was shown to have little effect on the ΔH^≠ value. The full set of effects of the R substituent contributes to the reactivity of ArNOO for 3-substituted aromatic nitroso oxides. In the case of 5-substituted ArNOO the Hammett-type relationship was obtain to describe inductive and resonant effects of R on the ortho-cyclization reactivity. The ortho-cyclization for 2-substituted nitroso oxides is a nontrivial example of the existence of an “inverted” steric effect, when an increase in substituent size accelerates intramolecular transformation. The substituent in position 6 also exhibits an “inverted” steric effect, but it is noticeably weaker than that for 2-R-C₆H₄NOO.     

Formation of Nitroso Oxides in the Photolysis of Aromatic Azides: Analysis of Products; Reaction Kinetics and Mechanism

The formation of nitroso oxides (ArNOO) IIa–IIc and IIf was observed in the flash photolysis of solutions of phenylazide (Ia), 4-methylphenylazide (Ib), 4-nitrophenylazide (Ic), and 4-bromophenylazide (If) in acetonitrile in the presence of oxygen, and the optical spectra of these nitroso oxides were obtained. The kinetics of generation (using IIa and IIc as examples) and decay of nitroso oxides IIa–IIc and IIf were studied. The activation parameters of the formation of IIa by the reaction of triplet phenylnitrene with molecular oxygen ( = (9.6±0.4)-(18±2)/2.303RT ( , 1 mol^-1s^-1;E _a,kJ/mol)) and the unimolecular isomerization of IIa into dioxaziridine ( = (9.0±0.8)-(56±)/2.303RT( ,1 mol^-1s^-1;E _a,kJ/mol)) were determined. The kinetics of formation of the molecular products of Ia photooxidation were studied using high-performance liquid chromatography. Nitrobenzene was the only stable reaction product (except for tars). A reaction scheme which is consistent with the experimental results was proposed for the photooxidation of Ia.     

Flash photolysis study of the reactivity of isomeric forms of arylnitroso oxides toward triphenyl phosphite

The kinetics of the reactions of phenylnitroso oxide and 4-CH₃O-, 4-CH₃-, and 4-Br-phenylnitroso oxides with triphenyl phosphite was studied in acetonitrile, benzene, and hexane by flash photolysis. The reaction occurs only with the trans-isomers of nitroso oxides. The value of the reaction rate constant increases with an increase in the electron-withdrawing power of substituents on the nitroso oxide aromatic ring, with the rate constant being almost the same in benzene and acetonitrile, and increasing by a factor of 2–3 in hexane. The temperature dependence for the decay rate constants of isomeric nitroso oxides in the presence of triphenyl phosphite was studied in acetonitrile.     

Kinetics of reactions between arylnitroso oxides and methyl vinyl ketone

The kinetics of the reactions of phenylnitroso oxide, (4-methylphenyl)nitroso oxide, (4-methoxyphenyl) nitroso oxide, 4-(N, N -dimethylamino)phenylnitroso oxide, (4-chlorophenyl)nitroso oxide, (4-bromophenyl) nitroso oxide, and (4-nitropenyl)nitroso oxide with methyl vinyl ketone in acetonitrile at 295 K was studied. With the use of 4-CH₃O-C₆H₄-NOO as an example, it was found that only the trans isomers of nitroso oxides entered into the reaction. The rate constants of the reactions of the trans isomers of nitroso oxides with methyl vinyl ketone were measured. A linear correlation between the logarithms of reaction rate constants and the electronic properties of substituents in the aromatic rings of nitroso oxides on the Hammett scale was established: ρ = 1.11 ± 0.08; r = 0.990.     

Effect of the structure of reactants on the reaction rate constants of aromatic nitroso oxides with olefins

The reactivity of phenylnitroso oxide, (p-methylphenyl)nitroso oxide, (p-nitrophenyl)nitroso oxide, (m-nitrophenyl)nitroso oxide, and (p-bromophenyl)nitroso oxide toward a number of olefins in acetonitrile at room temperature was studied using flash photolysis. It was found that the reaction rate constant decreased with decreasing energy of a molecular orbital with a maximum contribution from the atomic orbitals of carbon atoms in the C=C bond of olefins. This, along with a positive slope of the Hammett function for the reactions of substituted phenylnitroso oxides with 1-hexene and styrene, suggest an electrophilic character of these species. The temperature dependence of the rate constant of the reaction of phenylnitroso oxide with 1-hexene was studied: log A = 7.9 ± 0.4 [l mol^-1 s^-1]; E_a = 38 ± 2 kJ/mol.Translated from Kinetika i Kataliz, Vol. 45, No. 6, 2004, pp. 842–847.Original Russian Text Copyright © 2004 by Chainikova, Khursan, Safiullin.     

Chain processes in the reduction of aromatic nitroso compounds by triphenylphosphine in the presence of oxygen

The reduction of aromatic nitroso compounds by triphenylphosphine in the presence of oxygen is accompanied by the chain reaction proceeding due to the interaction of trans-isomers of nitroso oxides formed in this system with triphenylphosphine followed by the regeneration of the initial nitrosobenzene.     

A new intramolecular transformation of aromatic nitroso oxides

The possibility of intramolecular interaction of a nitroso oxide group with an aromatic ring is investigated at the UB3LYP/6-311+G(d,p) and G3MP2B3 levels of theory for a wide series of aromatic nitroso oxides. It is found that this reaction leads to the formation of a dioxazole cycle, its subsequent decay resulting in opening of the benzene ring and formation of nitriloxide and carbonyl functional groups. The activation enthalpy of the transformation of phenylnitroso oxide is 75.1 kJ/mol. It is shown that various sub-stituents at ortho-position (with respect to the nitroso oxide fragment) considerably lower the activation barrier of the investigated transformation, particularly in case of o,p-dimethoxyphenylnitroso oxide ΔH ^≠ = 43.7 kJ/mol. It is concluded that in the case of polyaromatic nitroso oxides, for which intramolecular cyclization is more typical (ΔH ^≠ ∼ 50 kJ/mol), a factor favoring the attack on the ortho-carbon atom is the stabilization of the product’s diene group due to its inclusion in the polyaromatic system. It is established that sum of these effects leads to a low activation barrier for the transformation of nitroso oxide that forms during the photooxidizing of 2-azido-1-methoxyphenazine, ΔH ^≠ = 19 kJ/mol. It is proposed that due to the low activation energy of some nitroso oxides, their intramolecular cyclization may be the primary channel of their unimolecular decay.     

The reaction of nitroso oxides with olefins: Concerted or nonconcerted addition?

The mechanism of the interaction of nitroso oxides (RNOO) with olefins was studied at MCQDPT2/6-311+G(3df, 2p)//CASSCF(10; 9)/6-311G(d) level of theory. The following reaction channels were considered: (1) (3 + 2)-cycloaddition and nonconcerted biradical addition of nitroso oxide (2) through the terminal oxygen atom and (3) through the nitrogen atom to the C=C multiple bond. It was shown for the cases of (A) cis/trans-HNOO + C₂H₄, (B) cis/trans-HNOO + C₂F₄, (C) cis/trans-PhNOO + C₂H₄, and (D) cis/trans-PhNOO + C₂H₃CH₃ model systems that the typical reaction of nitroso oxides with alkenes was cycloaddition. For olefins with a decreased electron density at the multiple bond, as in system B, a substantial contribution of the one-center mechanism with the formation of biradical intermediates is possible.     

Simple Synthesis of Quinoxalin‐2(1H)‐one N‐Oxides from N‐Aryl‐2‐nitrosoanilines and Alkylated Cyanoacetic Esters

N‐Aryl‐2‐nitrosoanilines, available from the reaction of N‐arylamines with nitroarenes, condense under alkaline conditions with alkylated derivatives of cyanoacetic esters furnishing quinoxalin‐2(1H)‐one N‐oxides in good to excellent yields. The reaction involves the condensation of the carbanion with the nitroso group leading to the nitrone intermediate, followed by intramolecular acylation of the amine function.     

Isomeric forms of arylnitroso oxides: Electronic spectra and reactivity

The electronic spectra were measured and the kinetics of unimolecular decomposition of the isomeric forms (cis and trans) of phenylnitroso oxide, (4-methylphenyl)nitroso oxide, (4-nitropenyl)nitroso oxide, (4-bromophenyl)nitroso oxide, 4-(N,N-dimethylamino)phenylnitroso oxide, and (4-methoxyphenyl)nitroso oxide in acetonitrile, benzene, and n-hexane was studied using flash photolysis. In all of the nitroso oxides except for 4-(N,N-dimethylamino)phenylnitroso oxide, the cis form absorbed in a shorter wavelength region and was more labile than the trans form. The difference between the reactivity of the two species increased on going from n-hexane to acetonitrile. The temperature dependence of reaction rate constants was studied for both of the isomeric forms. Unlike the trans isomer, the cis isomer almost did not react with tetramethylethylene.     

Kinetics and mechanism of the nitrosobenzene deoxygenation by trivalent phosphorous compounds

The reaction of aryl nitroso compounds with organic phosphines and phosphites in aerated media is a convenient non-photolytic procedure to generate aromatic nitroso oxides. The reaction rate constants and activation parameters of the key (for the proposed method of nitroso oxide generation) reaction of nitrosobenzene with tripenyl phosphite or para-substituted phosphines (4-RC₆H₄)₃P (R = MeO, Me, H, F), as well as that of para-methoxynitrosobenzene with triphenylphosphine in acetonitrile were determined by kinetic spectrophotometry and chemiluminescence. A significant transfer of the electron density to the nitroso compound occurs in the transition state of the reaction as was revealed using the Hammett correlation analysis and DFT calculations in the M06L/6-311+G(d,p) approximation. The introduction of the electron-donor substituent MeO into the para-position of PhNO decreases the reactivity of the nitroso compound by two orders of magnitude. The reactivity of triphenyl phosphite in the oxygen atom transfer reaction is lower by two orders of magnitude compared to that of triphenylphosphine. In the case of the reactions of PhNO with phosphines, the apparent rate constant depends on the oxygen content in the reaction medium.     

Reactivity of arylnitroso oxides to triphenylphosphine

The kinetics of reactions between phenylnitroso oxide, 4-CH₃O-, 4-CH₃-, or 4-Br-phenylnitroso oxide and triphenylphosphine in acetonitrile at 295 ± 2 K were studied using pulsed photolysis. Only trans-nitroso oxides enter this reaction. The rate constants of the reaction increase with increasing electron-acceptor properties of the substituent in the aromatic ring of nitroso oxide; they are on the order of 10⁵ to 10⁶ l mol⁻¹ s⁻¹. The extinction coefficient for trans-4-methylphenylnitroso oxide at 420 nm was estimated at 3.9 × 10³ l mol⁻¹ cm⁻¹.     

A revised mechanism of thermal decay of arylnitroso oxides

The electronic spectra were measured and the unimolecular decay kinetics of the isomeric forms (cis and trans) of 4-methoxyphenylnitroso oxide in acetonitrile, benzene, and hexane was studied using flash photolysis. The cis form absorbed in a shorter wavelength region and was more labile than the trans form. The difference between the reactivity of the two species increased on going from hexane to acetonitrile. The temperature dependences of reaction rate constants were studied for both isomeric forms. The analysis of products of flash photolysis of 4-methoxyphenyl azide in the presence of oxygen allowed for understanding the mechanism of thermal decay of nitroso oxides. It was shown that the trans nitroso oxide is converted into cis nitroso oxide. The latter undergoes an unusual ring cleavage reaction to form 4-methoxy-6-oxohexa-2,4-dienenitrile N-oxide derivative. We conclude that the nitro- and nitrosobenzenes, which are the main products of the steady-state photolysis of aromatic azides in the presence of oxygen, are formed by the photochemical transformation of the nitroso oxides.     

Kinetics of the mercury(II)‐catalyzed substitution of coordinated cyanide ion in hexacyanoruthenate(II) by nitroso‐R‐salt

The kinetics and mechanism of Hg²⁺‐catalyzed substitution of cyanide ion in an octahedral hexacyanoruthenate(II) complex by nitroso‐R‐salt have been studied spectrophotometrically at 525 nm (λ_max of the purple‐red–colored complex). The reaction conditions were: temperature = 45.0 ± 0.1°C, pH = 7.00 ± 0.02, and ionic strength (I) = 0.1 M (KCl). The reaction exhibited a first‐order dependence on [nitroso‐R‐salt] and a variable order dependence on [Ru(CN)₆^4?]. The initial rates were obtained from slopes of absorbance versus time plots. The rate of reaction was found to initially increase linearly with [nitroso‐R‐salt], and finally decrease at [nitroso‐R‐salt] = 3.50 × 10^?4 M. The effects of variation of pH, ionic strength, concentration of catalyst, and temperature on the reaction rate were also studied and explained in detail. The values of k₂ and activation parameters for catalyzed reaction were found to be 7.68 × 10^?4 s^?1 and E_a = 49.56 ± 0.091 kJ mol^?1, ΔH^≠ = 46.91 ± 0.036 kJ mol^?1, ΔS^≠ = ?234.13 ± 1.12 J K^?1 mol^?1, respectively. These activation parameters along with other experimental observations supported the solvent assisted interchange dissociative (I_d) mechanism for the reaction. © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 41: 215–226, 2009     

Regio‐ and Stereochemical Studies on the Nitroso‐Diels–Alder Reaction with 1,2‐Disubstituted Dienes

The regioselectivity of the nitroso‐Diels–Alder reaction between unsymmetrical acyclic dienes and Boc‐nitroso (Boc=tert‐butoxycarbonyl) reagent or the Wightman chiral chloronitroso reagents has been studied. With the Boc‐nitroso reagent, the selectivity is a consequence of steric effects at the C1‐position in the diene and electronic effects at the C2‐position in the diene. The combination of an unprotected hydroxyethyl side chain at C1 and an electron‐withdrawing group at C2 allows complete regioselectivity in favour of the proximal isomer. The same isomer was obtained exclusively with the chiral nitroso reagent with high enantioselectivities. A model based on steric effects is proposed.     

Reactions of arylnitroso oxides with substituted styrenes: Kinetics and products

The kinetics of the reactions of phenylnitroso oxide and 4-CH₃O- and 4-Cl-phenylnitroso oxides with a series of substituted styrenes (4-X-C₆H₄-CH=CH₂; X = H, CH₃O, Cl, CN) in acetonitrile at 22 ± 2°C was studied using the flash photolysis technique. It was shown for 4-CH₃O-C₆H₄NOO as an example that only the trans isomers of the nitroso oxides are involved in the reaction. There is a linear correlation between the logarithm of the rate constant and the electronic properties of the substituent in the nitroso oxide aromatic ring on the Hammett scale: ρ = 2.3 ± 0.3 (r = 0.993) for 4-CH₃O-styrene ρ = 2.03 ± 0.07 (r = 0.995) for styrene, and ρ = 1.77 ± 0.05 (r = 0.9996) for 4-Cl-styrene. Both the electron-donating and electron-withdrawing substituents in the aromatic ring of styrene increase its reactivity toward a given nitroso oxide. An analysis of the products of phenyl azide photooxidation in the presence of styrene showed that the product of phenylnitroso oxide [3+2]cycloaddition to the double bond of the olefin decomposes into benzalaniline and carbonyl oxide.     

Magtrieve™ (CrO2) and MnO2 mediated oxidation of aldoximes: studying the reaction course

Magtrieve™ (CrO₂) and MnO₂ mediated oxidation of aldoximes to nitrile oxides were studied in details. In presence of external radical source, TEMPO, these reagents did not furnish nitrile oxides, instead favoured deoximation to aldehydes. A common trend of deoximation was established from electronically tuned aldoximes, which is: aliphatic>aromatic>aldoximes with strong electron-withdrawing group, though the extent of deoximation was less in case of CrO₂. Above effects were not observed with chloramine-T and diacetoxyiodobenzene, reagents known to produce nitrile oxides via hydroximoyl halide or equivalent ionic intermediates. A putative reaction mechanism is proposed for MO₂ (M=Cr, Mn) mediated oxidation of aldoximes through formation of a nitroso-oxime tautomeric pair. Formation of nitrile oxide is possibly occurred from the oxime tautomer via a σ-type iminoxy radical intermediate. The deoximation process, dominating in presence of external radical environment, is explained following decomposition of the nitroso tautomer.     

Mechanism of autoreduction of 2,2,6,6-tetramethyl-1,4-dioxopiperidinium cation in alkaline medium

Autoreduction of 2,2,6,6-tetramethyl-1,4-dioxopiperidinium ion to nitroxyl radical in alkaline medium involves a number of parallel and consecutive reactions. The primary products of the reaction of 2,2,6,6-tetramethyl-1,4-dioxopiperidinium with hydroxide ion are three nitroso compounds and N-hydroxy-2,2,6,6-tetramethylpiperidine N-oxide. Isomerization of the nitroso compounds and elimination of acetone from the N-oxide give cyclic hydroxylamines which reduce the initial cation to nitroxyl radical, being oxidized to nitrones.     

Origins of the Enantio‐ and N/O Selectivity in the Primary‐Amine‐Catalyzed Hydroxyamination of 1,3‐Dicarbonyl Compounds with In‐Situ‐Formed Nitrosocarbonyl Compounds: A Theoretical Study

Chemoselective control over N/O selectivity is an intriguing issue in nitroso chemistry. Recently, we reported an unprecedented asymmetric α‐amination reaction of β‐ketocarbonyl compounds that proceeded through the catalytic coupling of enamine carbonyl groups with in‐situ‐generated carbonyl nitroso moieties. This process was facilitated by a simple chiral primary and tertiary diamine that was derived from tert‐leucine. This reaction featured high chemoselectivity and excellent enantioselectivity for a broad range of substrates. Herein, a computational study was performed to elucidate the origins of the enantioselectivity and N/O regioselectivity. We found that a bidentate hydrogen‐bonding interaction between the tertiary N⁺? H and nitrosocarbonyl groups accounted for the high N selectivity, whilst the enantioselectivity was determined by Si‐facial attack on the (E)‐ and (Z)‐enamines in a Curtin–Hammett‐type manner. The bidentate hydrogen‐bonding interaction with the nitrosocarbonyl moieties reinforced the facial selectivity in this process.     

Proline‐Tetrazole‐Catalyzed Enantioselective N‐Nitroso Aldol Reaction of Aldehydes with In Situ Generated Nitrosocarbonyl Compounds

A highly enantioselective method (up to 98 % ee) for the preparation of β‐amino alcohols was achieved by using the readily available proline‐tetrazole as the catalyst for the N‐nitroso aldol reaction of aldehydes with in situ generated nitrosocarbonyl compounds. The key to success of this reaction is the use of MnO₂ as an oxidant and catechol as a Brønsted acid additive.